Nicotine addiction, in the form of cigarette smoking, is the leading preventable cause of morbidity and mortality in the US. Although the prevalence of smoking has decreased substantially in the last few decades, it remains the single most prevalent form of addictive behavior. A growing body of research has shown that stimuli associated with nicotine administration (e.g., sight and odor of a cigarette) gradually acquire the capacity to elicit craving (urge to smoke) and other physiological responses (e.g., heart rate changes) that are presumed to contribute to the maintenance of smoking behavior. Recent research suggests that gender and intra-gender factors, such as menstrual cycle phase in women, may modulate the craving and physiological reactions elicited by smoking cues. Relatedly, the findings of our on-going SCOR protocol suggest that men and women may differ in their craving and physiological reactions to smoking and stress cues, and that these same reactions may differ among women smokers who are in different phases of their menstrual cycle. Additionally, a SCOR-funded pilot protocol has permitted us to establish procedures for, and determine the feasibility of, a study to manipulate the timing of quit attempts relative to menstrual cycle phase and to determine the impact on smoking cessation outcome. Building on our previous work, this application proposes a two-part research design, in which we first randomize 226 nicotine-dependent women aged 18-40 to receive a single-session, cue reactivity/impulsivity assessment in either the follicular or luteal phase of their menstrual cycle. In this session, standardized measures of cue reactivity and impulsivity will be obtained. Cue reactivity procedures will involve exposure to robust in vivo smoking cues and take place under conditions of nicotine deprivation. The second part of the study, using the same study sample, proposes a 2x2 randomized clinical trial, in which tinning of quit attempts (follicular vs. luteal menstrual cycle phase) is crossed with pharmacotherapy (transdermal nicotine patch vs. varenicline). Thus, our study represents a programmatic extension of our prior research on menstrual-related effects on smoking behavior, integrates a human laboratory cue-reactivity paradigm with a treatment outcome study, tests whether pre-treatment responses to smoking cues predict measures of treatment outcome, and examines potential interactions between timing of menstrual phase and type of treatment. This application fits well within the scope of the overall SCOR and specifically interdigitates with Component 3, which examines menstrual cycle effects on nicotine administration and reinstatement in a mouse model, and with Component 2, which examines cue-induced craving to cocaine in a clinical population. Results of this study may inform treatment-optimizing decision-making among women smokers.